Many human diseases including neurological diseases, diabetes, and diseases associated with aging are molecular and genetic in nature. To fundamentally understand these diseases and to discover pharmaceutical interventions, screening large libraries of reagents using assays in model genetic systems (including worms, flies, and fish) is not only a viable but fruitful approach. The current bottlenecks, however, are in the manual and semi-quantitative techniques such as visual screens or image-based screens, often limiting both the throughput of the experiments;in addition, it is practically impossible or very difficult to use large reagent libraries in conjunction with these assays. Our long- term objective is to develop and use engineering-enabled high-throughput and high-content methods to speed up the discovery processes using model organisms. The objective of this project is to develop a novel high-throughput quantitative method combining microfluidics and automation for studying genes involved in synaptic transmission functions. Genes and pathways emerging from this study could potentially become targets of therapeutics in neurological disorders. The approach is innovative because the technology developed here dramatically increases the capabilities of existing screening tools, and is widely applicable to a variety of problems in different experimental systems. The proposed research is significant because it fills a technology gap in high-throughput and high-content screens, and a knowledge gap in genes and pathways in synaptic transmission. PUBLIC HEALTH RELEVANCE: Synapse transmission is an important and active area of research linking genes to the functions of synapses and the nervous system. It has direct applications to many human diseases such as dysfunctional motor control and mental illnesses.